Fragment of secreted heat shock protein-90alpha (Hsp90alpha) as vaccines or epitope for monoclonal antibody drugs or target for small molecule drugs against a range of solid human tumors

一种小分子、抗体的技术，应用在抗肿瘤药、肽/蛋白质成分、含有效成分的医用配制品等方向，能够解决不可进化耐受等问题

Inactive Publication Date: 2013-12-04
UNIV OF SOUTHERN CALIFORNIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Csermely and colleagues argue that if chaperones are the only function nature has assigned to Hsp90, it is unlikely that the overproduction of such a single protein in cells will be well tolerated by evolution (9)

Method used

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  • Fragment of secreted heat shock protein-90alpha (Hsp90alpha) as vaccines or epitope for monoclonal antibody drugs or target for small molecule drugs against a range of solid human tumors
  • Fragment of secreted heat shock protein-90alpha (Hsp90alpha) as vaccines or epitope for monoclonal antibody drugs or target for small molecule drugs against a range of solid human tumors
  • Fragment of secreted heat shock protein-90alpha (Hsp90alpha) as vaccines or epitope for monoclonal antibody drugs or target for small molecule drugs against a range of solid human tumors

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Experimental program
Comparison scheme
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Embodiment 1

[0094] experimental method

[0095] Cell lines screened for deregulation of HIF-1α expression include: HBL-100 human breast epithelial cells, four human breast cancer cell lines (MDA-MB-231, MDA-MB-468, MDA-MB-435 and MCF- 7), M24 and M21 human melanoma cell lines, U251 and U87 human glioma cell lines, A172 human glioblastoma cell line, PC3 human prostate cancer cell line and A431 human skin cancer cell line. Native rat tail collagen type I was from BD Biosciences (Bedford, MA). Colloidal gold (gold chloride, G4022) was purchased from Sigma (St. Louis, MI). cDNAs encoding HIF-1α (wt), HIF-1α CA5 (constitutively active) and HIF-1αΔNBΔAB (dominant negative) were a gift from Dr. Gregg Semenza (Johns Hopkins University) and cloned into the lentiviral vector pPPLsin.MCS-Deco (20). shRNAs against human HIF-1α and HIF-1β were cloned in the lentiviral FG-12 system as previously described (39). Anti-HIF-1α antibody (#610958) and anti-HIF-1β antibody (#611078) were from BD Transduct...

Embodiment 2

[0115] Constitutive levels of HIF-1α are essential for breast cancer cell invasion

[0116] Applicants wished to identify tumor cell lines with deregulated expression of HIF-1α and to use this cell model to identify novel downstream effectors of deregulated HIF-1α that are essential for cell invasion in vitro and tumor formation in vivo. After screening various tumor cell lines (listed in the Materials and methods section), the applicants focused on the ER-negative and Ah-non-responsive breast cancer cell line MDA-MB-231, which was previously obtained from the pleural volume of a 51-year-old patient. Isolated from the fluid, it is invasive and metastatic (4). This choice also takes into account the following clinical data—approximately 30% of invasive breast cancer samples are hypoxic (10, 22). Untransformed human epithelial cells HBL-100 (13) were included as controls. Such as figure 1 In A, HIF-1α levels were undetectable in HBL-100 cells under normoxia (panel a, lane 1)....

Embodiment 3

[0119] Deregulation of HIF-1α in breast cancer leads to constitutive Hsp90α secretion

[0120] Applicants searched for targets of deregulated HIF-1α based on the following three criteria: 1) constitutively secreted by MDA-MB-231 cells; 2) under the direct control of deregulated HIF-1α and 3) for cells invasiveness is crucial. The applicants focused on the secretion of heat shock protein 90α (Hsp90α) based on the following evidence. First, Eustace et al. found that HT-1080 fibrosarcoma cells secreted Hsp90α (12). Second, hypoxia causes normal cells to secrete Hsp90α (19). Third, secreted Hsp90α mediates hypoxia-driven cell migration (42). Applicants therefore tested the possibility that deregulation of HIF-1α leads to secretion of Hsp90α which in turn leads to increased migration and invasiveness of MDA-MB-231 cells. Serum-free conditioned medium (CM) of HBL-100 and MDA-MB-231 cells cultured under normoxia or hypoxia was analyzed for the presence of Hsp90α. Such as figur...

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Abstract

The invention provides methods for treating HIF-1a-overexpressing human tumors, inhibiting HIF-1a-overexpressing tumor invasion and preventing tumor metastasis, and / or promoting tumor prophylaxis, using various types of inhibitors against the Hsp90a from the tumors.

Description

[0001] Related Application Cross Reference [0002] This application claims priority to US 61 / 391,776, filed October 11, 2010, the contents of which are incorporated herein by reference. [0003] government concession [0004] This invention was made with Government support under Grant Nos. RO1GM066193, RO1GM067100, GMAR67100-01, AR33625, and RO1AR46538 awarded by the National Institutes of Health. The US Government has certain rights in this invention. technical field [0005] The present invention relates to the treatment of HIF-1α overexpressing (ie constitutively present) tumors using inhibitors of Hsp90α or fragments thereof. Background technique [0006] All publications cited herein are incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/16A61K48/00
CPCA61K31/713C07K14/47C07K14/435G01N33/92G01N2333/70596C07K2317/76G01N2500/10A61K39/0005C07K16/18G01N33/57484A61P35/00A61P35/04
Inventor 栗卫戴维·T.·伍德利陈梅
Owner UNIV OF SOUTHERN CALIFORNIA
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